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meta-analysis28. Significant variation of the time- lines behind the progression of health to predisease, to acute disease, to chronic disease and through dis- ease mitigation most likely exists. Indeed, many genome-wide association studies are identifying scores of previously unknown susceptibility loci29 that suggest multiple forms of disease states likely exist. Experimental protocols which maximise the individual situation while providing aggregate information (ie ‘pseudo-N-of-1’ testing protocols) should, thus, be considered as the only tenable pro- tocols to use in R&D and treatment settings.
Figure 2
Irreversibility: An equine analogy illustrating that irreversible outcomes can
result from external influences on biological systems, and that targeting the primary cause of disease may limit further
disease but may not represent the same target(s) to reverse disease. Simply put, if an event occurs opening a pen gate and allowing a horse to escape, shutting the gate does limit other horses from escaping (ie, limiting disease
progression) but does nothing to get (or even prevents getting) the escaped horse
back in. A completely different gate may need to be designed
changes including cell differentiation and apopto- sis can be initiated when even small and transient deviations exceed certain thresholds22,23. Preclinical or clinical studies optimised on linear input-output formats may provide flawed data that do not adequately represent what happens on a systems-wide level. Attempts to address alterations in single or multiple system points (via selective- or non-selective-pharmacological agents, respectively) in timeframes that do not adequately allow the full system to ‘respond’ need to be seriously reconsid- ered as they would also not likely provide data that represent long-term outcomes.
Horseman #4: ‘‘Pseudo-N-of-1’ health and disease states’
Human health and disease populations have been traditionally defined according to blunt and grossly simplified population segments (eg anatomical pathology). Studies showing that significantly dif- ferent genetic and phenotypic states of monozygot- ic twins are the exception and not the rule, that variations up to hundreds-fold of certain copy num- ber variants can result in similar physiological states where variation of only a few percent from basal levels of other systems result in disease, and that individuals can significantly alter their own physiological states by simply altering their routine diet over time or are exposed to novel environmen- tal agents24-27 are just a few examples that help explain the finding that experimental power is not necessarily gained solely by increases in numbers of test subjects reviewed in, for example, the use of
12
Horseman #5: Narrative medicine best practices ‘Narrative medicine’ is defined as the validation of the experience of the patient, and the encourage- ment of creativity and self-reflection in the patient and physician through holistic (eg physical, emo- tional, societal, etc) descriptions of the patient’s life. Narrative medicine is experiencing resurgence in ever-widening circles, but major shortcomings in the type and quality of care of patients remain30. Critics have decried the industrialisa- tion and ‘professionalism’ (versus ‘personalisa- tion’) of medicine for decades, emphatically con- tending that medical training and practice settings have all but removed the human touch from what has historically been medicine’s primary focus: the treatment of an individual’s whole life story and how it relates to the person’s health. Indeed, con- centrating not just on their medical history, but their individual story that includes ancestors and friends, interests and spiritual orientation were the cornerstones of the medical profession. Clinical trial designs and practice settings that treat med- ical problems merely as problems to be solved, without taking into account the specific psycho- logical and personal history of the patient, will most likely fail; narrative medicine, on the other hand, will most likely succeed. This is not to say that narrative medicine best practice is not with- out potential ‘downsides’. For example, appropri- ate care and attention to a person’s suffering and concerns leads to extremely high ‘placebo respons- es’ – responses that indicate the power of the human mind, not its limitations. Indeed, it has been suggested the ‘placebo response’ should be redefined as the ‘meaning response’: the physio- logic or psychological effects of meaning on the origins or treatment of illness31-33. Clinical trial design must be altered, therefore, to accommo- date, not mitigate, such high ‘meaning response rates’ and pharmaceutical companies might do well to only conduct their trials at sites that prac- tice narrative medicine approaches.
Drug Discovery World Winter 2011/12
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